Vol. 14 •Issue 5
• Page 32
CE Offering
Soy Isoflavones for Postmenopausal Symptoms
An Examination Of Evidence
By Rebecca Hulem, NP, and Robert M. Blair, PhD
Continuing Education Offering: The goal of this article is to educate nurse practitioners about soy isoflavones. Nurse practitioners may obtain 2 contact hours by reading this article and earning a passing score on the test that follows. For immediate test results, take the quiz online at www.advanceweb.com/np.
How to Obtain Contact Hours by Reading This Article
Instructions: Nurse practitioners may receive 2 contact hours by reading the article noted below and earning a passing score on the accompanying quiz. To obtain credits:
1. Read the article "Soy Isoflavones for Postmeno-pausal Symptoms. An Examination of Evidence," carefully noting the tables and other illustrative materials provided to enhance your knowledge and understanding of the content.
2. Read each question and record your answers on the registration form provided.
3. Fill out the evaluation portion completely. You will not receive CE credit if this section is not completed.
4. Type or print your full name and address in the space provided on the registration form.
5. Forward the completed registration form with your check or money order for $10.00 payable to Merion Publications, or provide your credit card information. Quizzes are accepted up to 24 months from publication.
Continuing Education Credit: Merion Publications Inc. is approved as a provider of continuing education in nursing (Provider #011-3-H-04) by the Pennsylvania State Nurses Association, which is accredited as an approver of continuing education in nursing by the American Nurses Credentialing Center Commission on Accreditation, the California Board of Registered Nursing (Provider #CEP 13230) and the Florida Board of Nursing (Provider #CEP 3298). California and Florida participants must retain certificates for 4 years.
Answers to the posttest will be graded, and you will be advised of your score within 30 to 60 days of receipt of the completed test. A score of 70% or above comprises a passing grade.
A certificate will be awarded to participants who successfully complete the test. Participants who score less than 70% can re-test one time for no additional charge. No refunds are provided.
Objectives: The purpose of this article is to educate nurse practitioners about soy isoflavones for postmenopausal symptoms. After reading this article, the nurse practitioner should be able to:
• Describe the pathophysiology of symptoms in postmenopausal women and the available treatment options.
• Define soy isoflavones and the mechanism for their effects on menopausal symptoms.
• Discuss soy and isoflavone research and the safety of these substances in breast cancer patients.
• Discuss the importance of patient education about safe and appropriate intake of soy isoflavones.
Directions: On the registration form, check the box next to the best answer.
Given today's average life expectancy, most women can expect to live a third of their lives after menopause. As a result, the health concerns of women in the menopausal age range are an increasing priority for health care providers.1
The symptoms of menopause can range from mild to severe. The hot flash is considered the classic and most bothersome symptom.2,3 Because of the side effects and risks associated with conventional therapies for hot flashes, many women are exploring the use of botanical medicine and dietary supplements, including soy.4
Pathophysiology of Symptoms
A recent conference of clinical experts convened by the National Institutes of Health evaluated evidence about the relationship of a variety of symptoms to menopause. Interestingly, only vasomotor symptoms (hot flashes and night sweats), vaginal dryness and sleep disturbances were strongly correlated with the menopausal transition.5 Data about mood, cognitive problems, somatic symptoms, urinary incontinence, uterine bleeding, sexual dysfunction and quality of life were either not strongly associated with the menopausal transition or were insufficient to determine a causal relationship.5
Hot flashes are typically experienced as intense heat that starts in the chest and moves to the neck and face. They are often associated with sweating, chills and clamminess. These changes are the result of increases in skin temperature, peripheral blood flow and core body temperature.6 Hot flashes appear to be associated with estrogen withdrawal, neuroendocrine changes and the thermoregulatory system.7-11 A thermoregulatory zone, bound by upper and lower thresholds, exists where normal body temperature is regulated.12 When core body temperature crosses the upper and lower thresholds, sweating and shivering occur. Compared with asymptomatic postmenopausal women, symptomatic postmenopausal women have smaller thermoneutral zones, low sweating thresholds and high sweat rates.13,14 Small increases in core body temperature occur immediately before a hot flash.6
Estrogen withdrawal may alter endorphins and estrogen metabolites in the brain that lead to an increase in norepinephrine, which then acts to reduce the thermoneutral zone.10,11 This makes the thermoregulatory system more sensitive to minor changes in core body temperature that result in hot flashes.10,11
Treatment Options
Hormone replacement therapy (HT) was once considered the most effective way to manage menopausal symptoms and to prevent certain long-term health problems associated with aging.15,16 But the Women's Health Initiative showed that HT is not as beneficial as we believed — and that it is associated with risks.
Multiple treatment options are available to reduce hot flashes, with varied effectiveness.10,17-19 The most efficacious treatment is hormone therapy, which decreases the incidence of hot flashes by 80% to 90%.20,21 Other treatment options include lower-dose hormone therapy (Prempro, Femhrt), antidepressants, gabapentin (Neurontin), veralipride and clonidine (Catapres).22-31 Because many of these treatments are associated with adverse effects, lifestyle changes incorporated with or without alternative therapies is recommended as first-line treatment.18
Complementary and alternative medicine (CAM) use is surging among women entering menopause.32 A recent study of postmenopausal women who had stopped taking HT demonstrated that of the women whose menopausal symptoms resumed, 21% went back on HT, 11% tried other prescription medication, and 48% tried CAM.33 Soy was the predominate form of CAM used.33 Other studies of CAM use have documented soy use rates ranging from 7.4% to 33%.34-36
Soy Isoflavones
While soy has proven health benefits related to its protein and isoflavone components, the beneficial effects of soy on menopausal symptoms are believed to be due to the soy isoflavones alone (Figure 1). Soybeans contain three primary isoflavones that are present in their glycoside (sugar-containing) form: genistin, daidzin and glycitin.37,38 During digestion, beta-glucosidases of intestinal brush border and intestinal bacteria origin cleave the sugar moiety from the isoflavone glycosides, resulting in the formation of their respective aglycone forms: genistein, daidzein and glycitein.39-46 The metabolism and absorption of soy isoflavones is beyond the scope of this article and has been discussed extensively elsewhere.47-49
While soy and soy isoflavones can affect biological systems in a variety of ways (via tyrosine kinase inhibition, antioxidant functions, DNA topoisomerase inhibition and steroidogenic enzyme inhibition), the effects of soy isoflavones on menopausal symptoms apparently are mediated via estrogen receptor (ER) binding activities.50-62 The isoflavones in soy bind and activate ER-alpha and ER-beta.63-66 Binding of the soy isoflavones to ER-beta is generally more potent than binding to ER-alpha.64,65 Soy isoflavones may act more like a selective estrogen receptor modulator (SERM) than an estrogen, since genistein binds to ER more like raloxifene than estradiol.67,68
Soy for Menopausal Symptoms
Research about the potential benefits of soy on menopausal symptoms has been difficult to interpret due to differences in the types of products tested, differences in product formulations, and differences in study parameters. Recent critical reviews of the data have yielded varying interpretations.69-71 This article discusses separate soy studies, isoflavone studies and studies in breast cancer patients.
Soy Studies
Several studies have examined the effect of dietary soy on hot flashes.72-82 In most of these studies, reductions in hot flash frequency or score were associated with soy consumption; however, these reductions were not always significantly different from the placebo control group. For example, one study reported a reduction in hot flash frequency in both the soy and the casein placebo groups, with the soy group exhibiting a significantly greater reduction in daily hot flashes (45%) compared with the placebo group (30%).73 Another researcher demonstrated a 41.7% reduction in hot flashes (from 6.0 to 3.5 hot flashes per day) after soy consumption (45 g/day for 12 weeks) compared with a 24.5% reduction (from 5.3 to 4.0 hot flashes per day) after wheat flour consumption.72 In yet another study, postmenopausal women who consumed a soy beverage (60 g/day) exhibited a 42% reduction in hot flashes, while women who consumed a casein beverage reported only a 19% reduction in hot flashes.77 However, the differences between soy and placebo were not statistically different in either of these studies.
Similarly, other placebo-controlled trials found no statistically significant difference in hot flashes between soy and placebo groups, although other studies reported significant reductions in hot flash severity and significant improvement in vasomotor scores compared with placebo.74,75,78,82 The results of these studies are summarized in Figure 2.
While most studies have compared a soy intervention with a nonsoy control, one researcher compared three soy groups containing different isoflavone levels.80 In this 2-year intervention study, each group received 25 g soy protein per day with 4 mg or less, 42 mg or 58 mg isoflavones per day. When all study subjects were included, hot flashes were reduced 42% and 59% from baseline by the soy protein containing 42 mg and 58 mg isoflavones, respectively. However, the isoflavone-poor soy reduced hot flashes by 77%. In women who experienced four or more hot flashes per day, hot flashes dropped 76% with 4 mg or less of daily soy protein for 2 years, 69% with 42 mg, and 70% with 58 mg.80
While the majority of studies have examined hot flash frequency as a primary endpoint, some have also examined changes in overall menopausal symptom scores, quality of life and vaginal maturation. One study reported a 37% reduction in overall symptom score in the soy group compared with a 28% reduction in the wheat flour group — not a statistical difference.72 Soy consumption reduced overall menopause symptom scores by 59% in another study, but this was not significantly different from the 45% reduction observed in the placebo group.67 The data about vaginal maturation is mixed; some studies documented improvement with soy consumption and some showed no effect.72,74,83,84
Two recent studies investigated the effects of soy on postmenopausal quality of life. Women who consumed 25.6 g soy containing 99 mg aglycone isoflavones per day for 1 year did not have improved quality of life scores from baseline or compared with the milk protein placebo group.81 In contrast, another research team found that a similar level of soy consumption resulted in a 36% improvement in vasomotor symptoms, a 40% improvement in psychosocial symptoms, a 30% improvement in physical symptoms, and a 36% improvement in sexual quality of life.82 The placebo group reported improvements of 6%, 12%, 7% and 16%, respectively.82
Taken together, these studies demonstrate that dietary soy reduces hot flashes by an average of 40% to 45%. However, in some instances this reduction in hot flashes is not substantially different from the overall reduction observed with placebo. Similarly, soy consumption appears to reduce overall menopausal symptom scores, but only slightly more than the placebo effect. While improvements in vaginal health and quality of life have been observed, the data is inconsistent.
Isoflavone Studies
In addition to studies of soy protein or soy foods, several studies have examined the effect of extracted or purified isoflavones on hot flashes and other menopausal symptoms.85-99 Randomized, controlled trials of purified isoflavones have reported significant reductions in hot flash incidence or severity compared with baseline measures and placebo.86,88,89,91,92 In one study, postmenopausal women who took 50 mg isoflavones per day exhibited greater reduction in hot flashes (around 45%) compared with women who took placebo tablets (around 25%).86 Another research team treated postmenopausal women with 70 mg isoflavones per day for 4 months and observed a significant reduction in the percentage of change in hot flashes in the isoflavone group (61.2%) compared with the placebo group (20.8%).88 Researchers in another study observed a significant reduction (27%, from 11.3 ± 0.2 at baseline to 8.2 ± 0.5 after 4 months) in vasomotor symptom scores in the isoflavone group compared with the placebo group (1%, from 10.0 ± 0.4 to 9.9 ± 0.4).89
A 54-mg/day dose of genistein, the predominant soy isoflavone, can reduce hot flashes by 22% after 3 months, 29% after 6 months and 24% after 12 months beyond the placebo group.91 Similarly, another study reported that women's mean hot flash value dropped 57% after 6 months compared with baseline and compared with placebo (19%).92 Recent nonplacebo-controlled trials have also reported hot flash reductions ranging from 21% to 48%.87,96,98 These data are summarized in Figure 3.
In contrast to these data, several studies have not documented hot flash reductions significantly different from the placebo effect.85,90,94 In these studies, isoflavones reduced hot flashes or hot flash scores by 28% (18% in the placebo group), 53% (53% with placebo) and 27% (30% with placebo).85,90,94
In addition to assessing treatment-related changes in hot flashes, several studies have examined overall menopausal symptom scores as well as particular menopausal symptoms. One research team observed a greater reduction in symptom score in the isoflavone group (44.6 ± 1 to 24.9 ± 1.7, for a 44% reduction) compared with the placebo group (40.3 ± 1.3 to 41.6 ± 1.1, for a 3% increase).89 Other studies have documented reductions in overall menopausal symptoms of 32% and 43% with soy isoflavones.92,93 However, these reductions were not different from the 30% and 35% reported for the placebo groups in these trials.92,93 Nonplacebo-controlled clinical trials have also reported improvements in overall menopausal scores of 30% to 40% and approximately 80%.96,97 Another study further demonstrated that soy isoflavones maintained the vaginal maturation index, which decreased in the placebo group.92
Recent evidence suggests that initial hot flash frequency is associated with response to soy or soy isoflavones. Women who experience more than five hot flashes per day appear to experience a greater benefit from soy or isoflavone supplementation.80,91,95 A regression analysis of 13 published studies investigated the relationship between hot flash frequency and the effectiveness of soy or soy isoflavones.100 The results revealed a statistically significant relationship between initial hot flash frequency and treatment efficacy, indicating that women who had greater numbers of hot flashes received the greatest benefit.
On average, these studies documented an approximately 45% reduction in hot flashes when treated with soy isoflavones. It is important to note that some studies reported no statistical difference between soy and placebo treatments. It is unclear whether the effectiveness of soy isoflavones is associated with a specific formulation or a specific isoflavone; however, a recent analysis of the literature suggests that products with a higher genistein ratio are more effective at reducing hot flashes.99
Use in Cancer Patients
Breast cancer patients often experience more severe menopausal symptoms than other women.101,102 This appears to be primarily due to discontinuation of hormone therapy, chemotherapy-induced menopause and tamoxifen therapy.103-107 Due to these issues, many breast cancer survivors seek alternative therapies for hot flashes and other menopausal symptoms. A recent study examined the use of CAM by breast cancer patients for the alleviation of menopausal symptoms.108 Twenty-nine percent of breast cancer patients used alternative therapies compared with only 5% of the controls. Of the alternative therapies used, soy was the most prevalent. Twelve percent of breast cancer survivors took soy for menopausal symptoms compared with only 3% of the controls.108
Only a few trials have investigated the efficacy of soy or soy isoflavones for menopausal symptom relief in breast cancer patients.109-112 In a short-term crossover study in which breast cancer patients received 150 mg isoflavones per day for 4 weeks, hot flashes decreased compared with baseline in both the soy (25%) and placebo (34%) groups, but no significant differences between treatments were observed.109 Another study documented similar reductions in the number of hot flashes per day in breast cancer survivors who consumed a soy beverage containing 90 mg soy isoflavones per day for 12 weeks.110 In a separate 3-month trial, consumption of soy isoflavones had little effect on menopausal symptoms. The hot flash index dropped by 10% in the isoflavone group and 14.3% in the placebo group.111 Overall, menopausal symptoms decreased 15.5% in the isoflavone group and 14.7% in the placebo group. Another study reported a similar reduction in overall menopausal symptom scores in patients who consumed 70 mg isoflavones daily for 12 weeks.112
While these few studies suggest that soy isoflavones are less effective for hot flashes in women who have had breast cancer compared with unaffected women, soy is a good nutritional source of high-quality protein, has additional health benefits, and appears safe for breast cancer survivors.113-115 Overall, the literature suggests that moderate amounts of soy foods can be consumed by breast cancer survivors or those at high risk for breast cancer as part of a healthy diet.113-115 The safety of soy for breast tissue has also been supported by research in monkeys. No adverse effects were observed after monkeys consumed a human equivalent of 200 mg to 400 mg soy isoflavones per day for up to 3 years.116,117 This safety is also supported by a 2-year study in which soy consumption did not increase mammographic density in premenopausal women.118
Putting It Into Practice
A variety of soy foods are available. The most common are soy milk, tofu, miso, tempeh, soybeans and dry roasted soy nuts. Isoflavones are now sold as dietary supplements and used as food fortificants. There are also many soy-fortified products, including energy bars, burgers and soy protein beverages.
With so many choices, patient education about safe and appropriate intake of soy protein or isoflavones is important. A review of soy studies suggests that an appropriate intake is 15 g (range 10 g to 25 g) of soy protein or 50 mg aglycone (biologically active) isoflavones (range 30 mg to 100 mg) per day.119 It is important to emphasize a safe range because it is increasingly easy for women to ingest large amounts of both soy protein and isoflavones. I encourage my patients to always check food and supplement labels for information on how much soy protein or isoflavones are included.
The question most frequently asked when women decide to try soy protein and soy isoflavones to reduce their menopausal symptoms is: "How soon will I see results?" Every woman is different, and individual results vary. For relief of menopausal hot flashes and night sweats, a reasonable time frame is 4 to 8 weeks. Consistent use is necessary for optimum results.
For some women, ingesting soy protein for the first time may cause uncomfortable gastrointestinal side effects such as flatulence, bloating or constipation. Advise women to start with 10 g of soy protein per day and gradually increase to 25 g per day. This recommendation fits with the U.S. Department of Agriculture heart health claim that diets including 25 grams of soy protein a day may reduce the risk of heart disease.
As demonstrated in the literature and observationally, soy protein and soy isoflavones are a safe alternative for postmenopausal women to use in managing the symptoms of menopause. Nurse practitioners play a vital role in educating and counseling patients about the many benefits of incorporating soy protein and soy isoflavones for improved health, well being and quality of life.
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Rebecca Hulem is a women's health nurse practitioner and certified menopause clinician. She practices at The Women's Clinic in Los Angeles, Calif. She is the author of Feelin' Hot? A Humorous, Informative and Truthful Look at Menopause and provides menopause coaching services to women throughout the country. Her Web site is www.themenopauseexpert.com. Robert Blair is the research manager for Revival Soy. The company manufactures and markets soy food and beverage products.
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